The overall goal of this research is to demonstrate proof-of-principle for using bifunctional T-cell receptor (TCR)-based immunotherapeutics for the treatment of cancer. These high affinity TCRs will be used to target immunomodulatory proteins such as cytokines to tumors to eradicate malignant cells. The TCR portions of these fusion proteins are specfic for unmutated p53 peptides presented in the context of HLA-A2. Four such TCR-based fusion proteins have been constructed to deliver IL-2, IFN-gamma, GM-CSF, or IgG1 to malignant cells. The TCR/IL-2 and TCR/lgG1 fusion proteins have been fully characterized for MHC restricted peptide specific binding and bioactivity in vitro. The TCR/IFN-gamma and TCR/GM-CSF fusion proteins will be similarly characterized for MHC restricted peptide specific binding and bioactivity. The apparent serum half life and highest tolerated dose will be determined in Balb/C mice for each fusion protein. Finally, the anti-neoplastic and anti-metastatic activity of these TCR fusion proteins will be assessed in a model system using SClD mice implanted with human tumor cells. Successful completion of these studies should facilitate the development of TCR-based reagents for commercialization.